The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459-465.
PIM-1 is the protooncogene activated by murine leucemia virus (Provirus Integration site for Moloney murine leucemia virus—MoMuLV) that induces T-cell lymphoma [Cuypers, H. T., et. al. Cell, 1984, 37, 141-150].
The expression of the protooncogene produces a non-transmembrane serine/threonine kinase of 313 residues, including a kinase domain consisting of 253 amino acid residues. Two isoforms are known through alternative initiation (p44 and p33) [Saris, C. J. M. et al. EMBO J. 1991, 10, 655-664].
PIM-1, PIM-2 and PIM-3 phosphorylate protein substrates that are important in cancer neogenesis and progression. For example, PIM-1 phosphorylates inter alia p21, Bad, c-myb, Cdc 25A and eIF4B (see e.g. Quian, K. C. at al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).
Two PIM-1 homologs have been described [Baytel, D. Biochem. Biophys. Acta 1998, 1442, 274-285; Feldman, J. et al. J. Biol. Chem. 1998, 273, 16535.16543]. PIM-2 and PIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acid level. PIM-1 is mainly expressed in thymus, testis, and cells of the hematopoietic system [Mikkers, H.; Nawijn, M.; Allen, J.; Brouwers, C.; Verhoeven, E.; Jonkers, J.; Berns, Mol. Cell. Biol. 2004, 24, 6104; Bachmann, M.; Moroy, T. Int. J. Biochem. Cell Biol. 2005, 37, 726-730. 6115]. PIM-1 expression is directly induced by STAT (Signal Transducers and Activators of Transcription) transcription factors, and PIM-1 expression is induced by many cytokine signalling pathways such as interleukins (IL), granulocyte-macrophage colony stimulating factor (GM-CSF), α- and γ-interferon, erythropoietin, and prolactin [Wang, Z et al. J. Vet. Sci. 2001, 2, 167-179].
PIM-1 has been implicated in lymphoma development. Induced expression of PIM-1 and the protooncogene c-myc synergise to increase the incidence of lymphomagenesis [Breuer, M. et al. Nature 1989, 340, 61-63; van Lohuizen M. et al. Cell, 1991, 65, 737-752]. PIM-1 functions in cytokine signalling pathways and has been shown to play a role in T cell development [Schmidt, T. et al. EMBO J. 1998, 17, 5349-5359; Jacobs, H. et al. JEM 1999, 190, 1059-1068]. Signalling through gp130, a subunit common to receptors of the IL-6 cytokine family, activates the transcription factor STAT3 and can lead to the proliferation of hematopioetic cells [Hirano, T. et al. Oncogene 2000, 19, 2548-2556]. A kinase-active PIM-1 appears to be essential for the gp130-mediated STAT3 proliferation signal. In cooperation with the c-myc PIM-1 can promote STAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T. et sl., immunity, 1999, 11, 709-719]. PIM-1 also appears to be necessary for IL-3-stimulated growth in bone marrow-derived mast cells [Domen, J. et al., Blood, 1993, 82, 1445-1452] and survival of FDCP1 cells after IL-3 withdrawal [Lilly, M. et al., Oncogene, 1999, 18, 4022-4031].
Additionally, control of cell proliferation and survival by PIM-1 may be effected by means of its phosphorylation of the well-established cell cycle regulators cdc25 [Mochizuki, T. et al., J. Biol. Chem. 1999, 274, 18659-18666] and/or p21(Cip1/WAF1) [Wang Z. et al. Biochim. Biophys. Acta 2002, 1593, 45-55] or phosphorylation of heterochromatin protein 1, a molecule involved in chromatin structure and transcriptional regulation [Koike, N. et al, FEBS Lett. 2000, 467, 17-21].
Mice deficient for all three PIM genes showed an impaired response to hematopoietic growth factors and demonstrated that PIM proteins are required for efficient proliferation of peripheral T lymphocyes. In particular, it was shown that PIM function is required for efficient cell cycle induction of T cells in response to synergistic T-cell receptor and IL-2 signalling. A large number of interaction partners and substrates of PIM-1 have been identified, suggesting a pivotal role for PIM-1 in cell cycle control, proliferation, as well as in cell survival.
The oncogenic potential of this kinase has been first demonstrated in E μ PIM-1 transgenic mice in which PIM-1 over-expression is targeted to the B-cell lineage which leads to formation of B-cell tumors [van Lohuizen, M. et al.; Cell 1989, 56, 673-682. Subsequently PIM-1 has been reported to be over-expressed in a number of prostate cancers, erythroleukemias, and several other types of human leukemias [Roh, M. et al.; Cancer Res. 2003, 63, 8079-8084; Valdman, A. et al; Prostate 2004, 60, 367-371;
For example, chromosomal translocation of PIM-1 leads to overexpression of PIM-1 in diffuse large cell lymphoma. [Akasaka, H. et al.; Cancer Res. 2000, 60, 2335-2341]. Furthermore, a number of missense mutations in PIM-1 have been reported in lymphomas of the nervous system and AIDS-induced non-Hodgkins' lymphomas that probably affect PIM-1 kinase activity or stability [Pasqualucci, L. et al, Nature 2001, 412, 341-346; Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875; Gaidano, G. et al., Blood 2003, 102, 1833-184]. Thus, the strong linkage between reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.
Several other protein kinases have been described in the literature, in which the activity and/or elevated activity of such protein kinases have been implicated in diseases such as cancer, in a similar manner to PIM-1, PIM-2 and PIM-3.
There is a constant need to provide alternative and/or more efficacious inhibitors of protein kinases, and particularly inhibitors of PIM-1, PIM-2 and/or PIM-3. Such modulators are expected to offer alternative and/or improved approaches for the management of medical conditions associated with activity and/or elevated activity of PIM-1, PIM-2 and/or PIM-3 protein kinases.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Journal articles J. Med. Chem. 2005, 48, 1367-1383 by Russell et al and J. Med. Chem. 2005, Vol 48, No. 23, 7089 by Carling at al both disclose inter alia triazolophthalazine compounds of potential use as GABAA receptor agonists, which may be useful therefore as inter alia hypnotics (and therefore for treating sleep disorders) and muscle relaxants. However, these documents only relate to fused tricyclic compounds in which one of the cyclic moieties is bridged. Further, there is no mention that the compounds disclosed therein may be useful as kinase inhibitors.
International patent application WO 2005/041971 discloses inter alia fused tricyclic compounds that may bind to of α2δ-1 sub-units of Ca channels, and may therefore be useful in the treatment of inter alia psychiatric and mood disorders. International patent applications WO 99/025353 and WO 98/04559 disclose various compounds that may act as ligands for GABAA receptors, WO 98/04560 discloses those that may act as inverse agonists of GABAA receptors, UK patent GB 2345443 discloses inter alia tricyclic compounds, which may be of use in treating premenstrual syndrome, and international patent application WO 2005/041971 discloses various tricyclic compounds for use in the treatment of bipolar diseases and the like. All of these documents only disclose fused tricyclic compounds that necessarily have oxy substituents, and do not disclose the use of those compounds as kinase inhibitors.
U.S. Pat. No. 5,011,835 discloses inter alia fused tricyclic compounds that may be useful as bronchodilators and antiallergic agents, but does not disclose tricyclic compounds that are substituted with an aromatic substituent, nor does it mention that the compounds may be useful as kinase inhibitors.
European patents EP 0 104 506 and EP 0 029 130 both disclose inter alia tricyclic compounds that may be useful as bronchodilators, but does not disclose any that bear an aromatic substituent, nor does it disclose the potential use of those compounds as kinase inhibitors.
Journal article J. Het. Chem. 1988, 25(2), 393-8 by Branko et al discloses various tricyclic compounds, including those that contain an aromatic triazolopyridazine bicycle as an integral part of the tricycle. However, this journal article does not disclose that those compounds have a medical use, and further only discloses tricycles in which the ‘third’ ring fused to the triazolopyridazine bicycle contains an unsaturation (double bond).
European patent applications EP 0 548 923 and EP 0 562 439 disclose inter alia tricyclic compounds containing an aromatic imidazopyridazine bicyclic core or a [1,2,4]triazolo[1,5-b]pyridazine core. However, it does not disclose any tricyclic compounds containing a [1,2,4]triazolo[4,3-b]pyridazine core, nor does it mention that any of the compounds disclosed therein may be useful as kinase inhibitors.
European patent application EP 0 620 224 discloses inter alia [1,2,4]triazolo[4,3-b]pyridazines, but none in which such a bicycle is a sub-component of a fused tricyclic compound. Nor does this document disclose that the compounds therein may be useful as kinase inhibitors.
US patent application US 2003/0078277 discloses tricyclic compounds that may be useful as a corticotrophin, and therefore of use in the treatment of e.g. depression. However, this document does not primarily relate to [1,2,4]triazolo[4,3-b]pyridazines, nor does it disclose that the compounds therein may be useful as kinase inhibitors.
US patent application US 2007/0167453 discloses inter alia tricyclic compounds that may be useful as histamine-H3 receptor antagonists. However, this document does not specifically relate to [1,2,4]triazolo[4,3-b]pyridazines substituted with an amino moiety and an aromatic group. Further, this document does not mention that the compounds disclosed therein may be useful as kinase inhibitors.
International patent application WO 99/06404 discloses various fused tricyclic compounds containing a triazolopyridazine core, for use as phosphodiesterase 4 inhibitors. However, this document only relates to fused tricyclic compounds in which each of the three rings is aromatic.
International patent application WO 2008/109104 discloses various triazolopyridazines for use as Akt kinase inhibitors, but this document does not disclose any fused tricyclic compounds.
International patent applications WO 2009/060197 and WO 2009/040552 disclose various imidazopyridazine-based and imidazolothiadiazolo-based compounds, for use as certain protein kinase inhibitors. However, these documents do not mention fused tricyclic compounds containing a bicyclic aromatic triazolopyridazine core fused to a non-aromatic ring.